1. Field of the Invention
This invention relates to delivery systems for active ingredients, and, more particularly, to a water-soluble delivery system for pharmaceutical, nutritional and cosmetic active ingredients, which includes a purified Shilajit composition obtained by extraction from native Shilajit containing a carrier which is purified fulvic acid, and, wherein the active ingredient is added to and present in voids of the carrier.
2. Description of the Prior Art
Native Shilajit is a blackish-brown exudation, of variable consistencies, obtained from steep rocks of different formations found in the Himalayas at altitudes between 1000-5000 m, from Arunachal Pradesh in the East, to Kashmir in the West. Shilajit also is found in other mountain ranges of the world, e.g. Afganisthan (Hindukush, Badakh-Shan), Australia (Northern Pollock Ranges), and in the former USSR (Tien-Shan, Pamir, Caucasus, Ural). Native Shilajit is believed to arrest aging and also produce rejuvenation, two important attributes of an Ayurvedic rasayan medicine. Considerable controversy, however, has existed in the literature concerning the nature and chemical character of Shilajit. It has been variously described as a bitumen (asphalt), a mineral resin, a plant fossil, a substance of mixed plant and animal origin, or an inorganic substance.
Generally, native Shilajit contains two classes of organic compounds, namely, (a) humic substances and (b) non-humic organic metabolites. Humic substances are the the major organic constituents of native Shilajit, present in an amount of about 80-85% therein; these substances have molecular weights ranging from several thousand for humic acids (HAs), to up to several million for polymeric humins (HMs) and only a few hundred for its fulvic acid (FAs) component. Humic substances also are found in soils and sediments distributed over the earth""s surface, occurring in almost all terrestrial and aquatic environments. Sedimentary rock humic substances are produced by the interactions of marine fossils, plants, algae and mosses (bryophtes) with microorganisms, by a process known as humification. Humification of latex-and resin-bearing plants is primarily responsible for the production of water-soluble humic substances.
The non-humic substances of Shilajit are low molecular weight (Mw) compounds of marine fossil, plant and microbial origin, occurring in and around Shilajit-bearing rocks. The remaining non-humic organic masses in Shilajit comprise a mixture of low Mw aromatic, aliphatic alicyclic, and heterocyclic (N- and S-containing) compounds. Of particular biological interest are low Mw oxygenated dibenzo-xcex1-pyrones (DBP) and hydroxyacetophenones (HAPs).
The ancestral origin of Shilajit now has been established as invertebrate fossils of the phylum: Mollusca, of the Mesozoic period (60-200 million years ago). Shilajit arises from the continental drift and plate tectonic effect, reached from the ocean-bed to sedimentary mountain top; and by bacterial interaction-humification which formed Shilajit humus-paleohumus. However, native Shilajit material varies considerably with respect to quality and the amount of bioactive materials therein. Furthermore processing of native Shilajit involves very complicated and tedious procedures. Recently, collection of good quality native Shilajit material has been improved so that, correspondingly, the output of a purified Shilajit product can be expected to be much improved.
The biological effects of Shilajit are believed to be due to the two distinct classes of bioactive compounds, namely: (i) DBPs, both mono- and bis-compounds thereof, in free and metal-ion conjugated forms; and (ii) fulvic acids (FAs) from Shilajit-humic substances, which function as a carrier for the bioactive DBPs. However, native Shilajit rhizospheres from different origins suffer from the presence of only small amounts of such bioactive compounds. Large amounts of contaminants, e.g. high Mw polymeric quinones, humins (HMs), and inorganic substances; however, are present. Shilajit rhizospheres also are heavily infested at its periphery with a large array of microorganisms, some of which are producers of mycotoxins. Thus, the potential risk of ingesting Shilajit in its native form, or only after rudimentary purification, with no control or defined standards, is quite apparent.
The prior art in this field is described in the xe2x80x9cInformation Disclosure Statementxe2x80x9d, attached hereto; these references are located in the related co-pending patent application. Other cumulative prior art is exemplified by the following references:
(1) S. Ghosal et al, Phytotherapy Res., 1991, 5, 211.
(2) S. Bhaumik, S. Chartopadhyay and S. Ghosal, Phytotherapy Res., 1993, 7, 425.
(3) Y. C. Kong et al, Int. J. Crude Drug Res., 1987, 25, 179.
(4) S. Ghosal, S. K. Singh and R. S. Srivastava, J. Chem. Res., 1988, 196.
(5) M. V. S. Sultanbawa, Tetrahedron, 1980, 36, 1465.
(6) S. B. Scharya et al, Indian J. Exp. Biol., 1988, 26, 775.
(7) S. Ghosal et al, Phytotherapy Res., 1989, 6, 249.
Accordingly, it is an object of this invention to provide a purified water-soluble delivery system for active ingredients such as pharmaceutical, nutritional and cosmetic ingredients using a purified fulvic acid carrier having voids therein into which an active ingredient can be incorporated for effective and controlled delivery of the active therefrom.
Another object of this invention is to provide such a delivery system which can augment the bioavailability of drugs for the user.
A feature of the invention is the provision of a stable delivery system including a purified fulvic acid carrier having predetermined molecular weight and void sizes which can accept different active ingredients advantageously to deliver and release them smoothly at cell-receptor sites.
Another feature of the invention is the enhanced water solubility of active drug ingredients.
These and other objects and features of the invention will be made apparent from the following description thereof.
What is provided in this invention is a stable, water-soluble delivery system which includes (a) a purified Shilajit composition preferably containing at least 40% by weight of purified fulvic acid carrier, obtained by extraction of native Shilajit so that the fulvic acid carrier is substantially without bioactive components therein. The purified fulvic acid carrier is characterized by having a sponge-like structure punctured by voids of about 200-1000 xc3x85 in diameter and a molecular weight, {overscore (M)}n, of about 700-2500, ({overscore (M)}n is a number average molecular weight); and (b) an active material, e.g. a water-insoluble ingredient, added to and filling voids in the purified fulvic acid carrier.
Preferably, the purified fulvic acid carrier has an E4/E6 absorption ratio of about 6-10, at xcex 465/665 nm.
Most preferably, the delivery system of the invention potentiates the bioactivity of a drug, nutritional or cosmetic ingredient incorporated into the voids of the purified fulvic acid carrier.
Still most preferably, the active ingredient suitably is present in an amount of about 0.5 to 40% by weight of the fulvic acid carrier.
The difference between Shilajit-based fulvic acid (FAs) and alluvial soil-derived fulvic acids lies in the core structures of the fulvic acids (FAs) in these compositions. Shilajit-FAs contains 3,8-oxygenated dibenzo-xcex1-pyrone as the core nucleus, which, upon repeated oxidation, and Michael addition reactions by nucleophile-containing oxygen, nitrogen and carbon ions, in association with various lipid moieties, produce a multiplayer micellar structure. In contrast, alluvial soil-FAs are composed essentially of aromatic hydroxy acids and polyphenols derived from phenolic oxidations. Both these FAs contain different metal ions, especially Fe, Co, Zn, Ca, etc., associated with the FAs. The metals in Shilajit-FAs are well-organized, multicentered, metal-ion associated products which, in the case of iron, maintains the metal in the reduced state and produce different iron-containing enzymes. Such trace ion-metal associations are not possible for soil-FAs because they have a much less organized heteropolycondensate structure whose micellar structure is irregular.
Another unique feature of Shilajit-FAs is that it is of endogenous origin produced by animal systems. These systems meet the essential need of bioavailability of trace metals and minerals, which serve as a carrier of essential nutrients in the living animal body. By contrast, soil-FAs, being exogenous in origin, do not contribute to those essential needs of animals.
Shilajit-FAs also contains oligomeric (di, tri, tetra) dibenzo-xcex1-pyrones, which scavenge free radicals and free metal ions, to become a soft-spin radical. In contrast, soil-FAs contain only esters of phenolic acids which do not have the antioxidant activity possessed by Shilajit-FAs.
Significantly, acylated DBP, with a lipid chain, are present in Shilajit-FAs; these actives behave like a liposome (polymicellar structure) which can act as an efficient carrier molecule. The phenolic acid esters present in soil-FAs do not possess these characteristics.
Thus, in accordance with the invention, the purified fulvic acid carrier constituent of native Shilajit, without toxic components, and substantially without bioactive constituents in the voids of the carrier, is provided by a defined extraction procedure from native Shilajit.
The purified Shilajit composition containing the purified fulvic acid carrier is obtained by an extraction procedure from native Shilajit rock exdudate, according to the following steps:
(a) powdering native Shilajit exdudate and dissolving it in water as solvent,
(b) filtering the mixture to remove insoluble substances,
(c) evaporating water from the filtrate to obtain a brown viscous residue,
(d) extracting the residue with a hot organic solvent, e.g. methanol, to obtain both a soluble fraction and an insoluble Shilajit-humic fraction,
(e) adding dilute aqueous NaOH to the insoluble Shilajit-humic fraction to precipitate polymeric quinones,
(f) acidifying the alkaline filtrate to a pH below about 3 to precipitate humic acids, leaving a brown acidic solution of fulvic acids,
(g) fractionating the acidic solution by passing it over activated carbon to provide a solution of low-to-medium Mw fulvic acids,
(h) passing the fulvic acid solution through a H+ ion-exchange resin to concentrate the fulvic acids in solution, and
(i) evaporating the solution.
The thus-obtained extraction product is a purified Shilajit composition preferable containing at least 40% by weight of purified fulvic acid carrier, and it is substantially without bioactive components therein. The fulvic acid has a sponge-like structure punctuated by voids of about 200-1000 xc3x85 in diameter and an {overscore (M)}n of about 700-2500. The active material then is added to the carrier to fill voids in its structure, thus-forming the desired delivery system. Upon dissolution in water, the active ingredient is released to perform its intended active function, e.g. a pharmaceutical, nutritional or cosmetic function.
A. The Active Ingredient (Pharmaceutical, Nutritional and Cosmetic Ingredients)
Any ingredient used to treat or affect the body, both topical and systemic, can be incorporated as the active agent into the polymeric carrier of this invention. An active ingredient thus includes drugs, nutrients, cosmetics, cosmecuticals, diagnostic agents, or a salt, isomer or derivative thereof, and mixtures thereof.
As used herein, the term xe2x80x9cdrugxe2x80x9d or any other similar term, means any chemical or biological material or compound suitable for administration by the methods previously known in the art and/or by the methods taught in the present invention that induces a desired biological or pharmacological effect, which may include but is not limited to (1) having a prophylactic effect on the organism and preventing an undesired biological effect such as preventing an infection, (2) alleviating a condition caused by a disease, for example, alleviating pain or inflammation caused as a result of disease, (3) either alleviating, reducing, or completely eliminating a disease including actinic aging of the organism and/or (4) protecting skin from photodamage. The effect may be local, such as providing for a local anesthetic effect, or it may be systemic. This invention is not drawn to novel drugs or to new classes of bioactive agents. Rather it is limited to the compositions and methods of delivery of agents that exist in the state of the art or that may later be established as active agents and that are suitable for delivery by the present invention. Such substances include broad classes of compounds normally delivered into the body by systemic or topical route. In general, this includes but is not limited to: anti-infectives such as antibiotics and antiviral agents; analgesics and analgesic combinations; anorexics; anthelmintics; antiarthritis; antiasthamatic agents; anticonvulsants; anticancer, antidepressants; antidiabetic agents; antidiarrheals; antihistamines; anti-inflammatory agents; antimigraine preparations; antinauseatics; antineoplastics; anti-Parkinson drugs; antipruritics; antipsychotics; anti-cancer agents; antipyretics; antispasmodics; anticholinergics; sympathomimetics; xanthine derivatives; carodiovascular preparations including potassium and calcium channel blockers, beta-blockers, alpha-blockers, and antiarrhythmics; antihypertensives; diuretics and antidiuretics; vasodilators including general coronary, peripheral and cerebral; central nervous system stimulants; vasoconstrictors; cough and cold preparations, including decongestants; hormones such as estradiol and other steroids, including corticosteroids; hypnotics; immunosuppressives; muscle relaxants; parasympatholytics; psychostimulants; sedatives; tranquilizers; sunscreens; anti-aging ingredients. By the method of the present invention, both ionized and nonionized pharmaceutical, nutritional or cosmetic actives may be delivered, as can they be either high or low molecular weight. Also included in the scope of these terms are nucleic acids, such as DNA, RNA, and oligonucleotides.
As used herein, xe2x80x9ceffective amountxe2x80x9d means an amount of a drug or bioactive or agent that is non-toxic but sufficient to provide the desired local or systemic effect and performance at a reasonable benefit/risk ratio attending any pharmaceutical, nutritional or cosmetic treatment.
As used herein, xe2x80x9cpeptidexe2x80x9d means peptides of any length and includes proteins. The terms xe2x80x9cpolypeptidexe2x80x9d and xe2x80x9coligopeptidexe2x80x9d are used herein without any particular intended size limitation, unless a particular size is otherwise stated. Typical of peptides that can be utilized are those selected from the group consisting of oxytocin, vasopressin, adrenocorticotropic hormone, epidermal growth factor, prolactin, or luteinising hormone releasing hormone, growth hormone, growth hormone releasing factor, insulin, somatostatin, glucagons, interferon, gastrin, tetragastrin, pentagastrin, urogastroine, secretin, calcitonin, enkepalins, endorphins, angiotensins, rennin, bradykinin, bacitracins, polymixins, colistins, tyrocidin, gramicidines, and synthetic analogues, modifications and pharmacologically active fragments thereof, monoclonal antibodies and soluble vaccines. The only limitation to the peptide or protein drug, which may be utilized, is one of functionality.
As used herein, a xe2x80x9cderivativexe2x80x9d of a carbohydrate includes, for example, an acid form of a sugar, e.g. glucuronic acid; an amine of a sugar, e.g. galactosamine; a phosphate of a sugar, e.g. mannose-6-phosphate; and the like.
As used herein, xe2x80x9cadministeringxe2x80x9d and similar terms mean delivering the composition to the individual being treated such that the composition is capable of being circulated systemically to the parts of the body where the composition binds to targeted cells and is taken up by endocytosis. Thus, oral subcutaneous, intramuscular, or intravenous administration, or intraperitoneal administration preferably administers the composition to the individual by topical or systemic administration. Injectables for such use can be prepared in conventional forms, either as a liquid solution or suspension or in a solid form suitable for preparation as a solution or suspension in a liquid prior to injection, or as an emulsion. Suitable excipients include, for example, water, saline, dextrose, glycerol, ethanol, and the like; and if desired, minor amounts of auxiliary substances such as wetting or emulsifying agents, buffers, and the like can be added.
B. The Carrier
The fulvic acid carrier in this invention is based on naturally occurring, toxicologically safe metabolites (e.g. 3,8-dihydroxy-dibenz-xcex1-pyrone, DBP, 4xe2x80x2 methoxy-6-carbomethoxybiphenyls, MCB). The purified fulvic acids (FAs) in this invention are polymeric units of 3,8-oxygenated dibenz-xcex1-pyrone repeat units having the general formula: 
A suggested sequence for the formation of fulvic acid in nature is given below: 
where: Nu=a nucleophile, e.g . RO, RNHxe2x88x92, RCO2xe2x88x92etc.
In this invention, generally higher mol. wt. (e.g. {overscore (M)}n 2000) purified fulvic acid carriers are used for delivering high molecular wt. drugs, e.g. polypeptides, etc., which otherwise would not cross the membrane barrier. Low mol. wt. fulvic acid (e.g. {overscore (M)}n less than 1000, voids 200-500 xc3x85) is preferred for delivering purified low molecular weight drugs.
In the delivery system of the invention, the active ingredient is physically and/or chemically bound within the voids of the fulvic acid carrier by hydrophobic bonding, ligand-complex/chelation, reversible covalent bonding and/or charge-transfer complexes.
The active ingredient is incorporated into its fulvic acid carrier by simple blending, e.g. by stirring in a common solvent, or by dry-powder admixture, with or without an added third component.
The invention especially provides a delivery system composition of pharmaceutical, nutritional or cosmetic compounds for oral or topical administration, particularly a water-insoluble ingredient, using a purified Shilajit composition containing at least 40% by weight of purified fulvic acid as defined hereinbefore.
The invention also provides a method of administration of such composition to a subject, which comprises administering it orally, topically or parentally.
The formulations according to the invention may be used for known indications of the particular pharmaceutical, nutritional or cosmetic compound incorporated therein.
The effective amounts of pharmaceutical, nutritional or cosmetic compound and of the formulation to be administered depends on a number of factors, e.g. the condition to be treated, the desired duration of treatment, and the rate of release of the compound.
The desired formulations may be produced in a known manner. The amount of the pharmaceutical, nutritional or cosmetic active agent required and the release rate thereof may be determined on the basis of known in vitro or in vivo techniques, e.g. how long a particular active agent concentration in the blood plasma or on skin remains at an acceptable level. The degradability of the matrix may also be obtained by in vitro or especially in vivo techniques, for example wherein the amount of matrix materials in the subcutaneous tissue is determined after particular time periods.
Suitably the active ingredient is present in an effective amount, preferably about 0.5 to 40% by weight of the purified fulvic acid carrier.
The invention will be described hereinafter with reference to the following examples.